RT Journal Article
SR Electronic
T1 Variability in the Analgesic Response to Ibuprofen Following Third-Molar Extraction is Associated with Differences in Activation of the Cyclooxygenase Pathway
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 467407
DO 10.1101/467407
A1 Katherine N. Theken
A1 Elliot V. Hersh
A1 Nicholas F. Lahens
A1 Hyo Min Lee
A1 Eric J. Granquist
A1 Helen Giannakopoulos
A1 Lawrence M. Levin
A1 Stacey A. Secreto-Dankanich
A1 Gregory R. Grant
A1 John A. Detre
A1 Garret A. FitzGerald
A1 Tilo Grosser
A1 John T. Farrar
YR 2018
UL http://biorxiv.org/content/early/2018/11/11/467407.abstract
AB The analgesic efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) has long been recognized to be limited by substantial interindividual variability in pain relief, but the underlying mechanisms are not well understood. We performed pain phenotyping, functional neuroimaging, pharmacokinetic/pharmacodynamic assessments, inflammation biomarkers, and gene expression profiling in healthy subjects who underwent surgical extraction of bony impacted third molars, in order to characterize factors associated with heterogeneity in response to ibuprofen.Subjects were treated with rapid-acting ibuprofen (400 mg; N=19) or placebo (N=10) in a randomized, double-blind design. Compared to placebo, ibuprofen-treated subjects exhibited greater reduction in pain scores, alterations in regional cerebral blood flow in brain regions associated with pain processing, and inhibition of ex vivo cyclooxygenase activity and urinary prostaglandin metabolite excretion as indices of biochemical drug action (p<0.05). As expected, ibuprofen-treated subjects could be stratified into partial responders (N=9, required rescue medication within the dosing interval) and complete responders (N=10, no rescue medication). This was also reflected by differences in pain scores (p<0.01) as early as 30 minutes following drug administration (p<0.05). Variability in analgesic efficacy was not associated with demographic or clinical characteristics, ibuprofen pharmacokinetics, metabolizing enzyme genotype, or the degree of cyclooxygenase inhibition by ibuprofen. However, complete responders had higher concentrations of inflammatory biomarkers in urine and serum, than partial responders. Specifically, a stable urinary prostaglandin E2 metabolite, serum TNFα and IL-8 were higher in patients who did not require rescue medication compared those who did (p < 0.05). RNAseq gene expression analysis in PBMCs collected after surgery and ibuprofen administration showed enrichment of inflammation related pathways among genes differentially expressed (q < 0.2) between complete and partial respondersThese findings suggest that patients who receive substantial pain relief from ibuprofen have a more pronounced activation of the prostanoid biosynthetic pathway and regulation of the inflammatory pain phenotype differs from those patients who are insufficiently treated with ibuprofen alone and may require an opioid or other therapeutic intervention.